Phenthiazine compounds



United States Patent 3,320,247 PHENTHIAZINE COMPOUNDS Herbert Arnold and Rolf Rebling, Bielefeld, Norbert Brock, Uber Bielefeld, and Hans-Dieter Lenke, Bielefeld, Germany, assignors to Asta-Werke AG, Chemische Fahrik, Brackwede, Germany, a corporation of Germany No Drawing. Filed Feb. 10, 1965, Ser. No. 431,712 Claims priority, application Germany, Feb. 28, 1964,

13 Ciaims. (Cl. 260-243) wherein R is a member selected from the group consisting of methyl and ethyl and n is a numeral selected from the group consisting of 2 and 3 and preferably is 2, and salts thereof with pharmacologically acceptable acids. The preferred salts are the hydrochlorides.

The new compounds may be produced in accordance with the present invention by the following N-alkylating methods:

(A) Subjecting a phenthiazine derivative of the general Formula II wherein X is the residue of a reactive ester, preferably halogen or the residue of a sulphuric or sulphonic acid ester, to reaction with an imidazolidone derivative of the general Formula III wherein R and n have the same meaning as in the general Formula I;

(B) subjecting 3-chloro-phenthiazine to reaction with an imidazolidone derivative of the general Formula IV wherein R and n have the same meaning as in the general Formula I and X has the same meaning as in the general Formula II;

(C) Subjecting a phenthiazine derivative of the general Formula V 3,320,247 Patented May 16, 1967 ice to reaction with an imidazolidine derivative of the general Formula VI I o N-R VI wherein n and R have the same meaning as in the general Formula I and Hal is a halogen.

The process according to the present invention may be preferably carried out in the presence of an inert organic solvent such as for instance an aromatic hydrocarbon, preferably toluene or Xylene, or an ether, preferably dioxane. Depending upon the nature of the reaction components preferably triethylamine is used as the necessary acid binding agent or an alkali metal derivative such as for instance sodium amide is used as condensing agent. The reaction is carried out at an elevated temperature, such as the boiling point of the applied solvent.

The imidazolidone derivatives of the general Formulas III and IV which are used as starting materials in the processes according to the present invention are not known in the prior art. They may be obtained by subjecting an oxazolidone to reaction with an isocyanate according to the following equation wherein R and n have the same meaning as in the above general Formula I and Hal is a halogen atom, preferably ,a chlorine atom, according to copending application Serial No. 388,983, filed on August 5, 1964, and entitled Process for the Production of Imidazolidones, and subjecting the 1-alky1-3-(w-ha1ogenoalky1)-imidazolidones VI thus obtained in manners known per se to reaction with piperazine to yield compounds of the general Formula III, or, respectively, with mono-substituted piperazines to compounds of the general Formula IV. In place 0w piperazine, .a mono-N-carboxy-piperazine of the Formula VII HN N-oo-o R1 group, may be used as reaction component; in this case,

the carbalkoxy group has to be split off before the compound is further reacted. The phenthiazine derivative of the general Formula V may be obtained for instance according to the published German patent application DAS 1,037,461 by subjecting 3-chloro-10-('y-ch lor0propyl)- phenthiazine to reaction with piperazine. In this case, too, a mono-N-carbalkoxy-piperazine of the Formula VII may be used in place of piperazine whereafter the carbalkoxy group is split off in the resulting product in manners known per se.

The process according to the present invention is illustrated by the following examples wherein the compounds are named according to the nomenclature used in Beilsteins Handbuch der Organischen Chemie (Handbook of Organic Chemistry).

Example 1.N-[B-(I-met/zyl-2-0x0-imidaz0lidyl) ethyl]-piperazine 32.5 g. of 1-methyl-3-j3-ch1oroethyl-imidazolidone-(2) fractionated in a high vacuo. Thus, the 3-chl0ro-10-[1- (1-rnethyl-2"-oxo-3"-ethyl-imidazolidyl) 4' piperazino-n-propyll-phenthiazine base is obtained. B.P. approx. 260 C. Yield: 18.5 g. (51.33% of the theoretiare dissolved in 200 cc. of dioxane. After having added 5 l) t r t 3 gf mono N cafbethoxyrpiperallne and For preparing the dihydrochloride, the distilled base is 2042 of triethylamine, the reaction miXtufe iS heated dissolved in anhydrous ether and ethereal hydrogen to boiling under reflux for 8 hours. Thereafter, the p echloride is added to this solution with cooling. The pre- Cipitated tl'iethylamine hydrochloride s filtered Q and cipitated dihydrochloride is filtered oil and preferably rethe dioxane is distilled off in a vacuo. h sl i8 crystallized from dioxane or acetone mixed with a small distilled in a high vacuo. B.P. 2 203207 C. amount of methanol, F 255 C Yield: 45 g. (79.11% of the theoretical). I 30 g. of the thus obtained N-[l-methyl-imidazolidonef z f f j zi'fj ff' 3' 5? 2; (2)-ethyl-(3)]-N'-(carbethoxy)-piperazine are dissolved y p p P W p Z in 250 cc. of a 10% alcoholic solution of potassium hy- 22 g. (0.071 mol) of 3-ch1oro-10-(vp pyU- droxide and heated to boiling under reflux for 15 hours. phenthiazine are dissolved in 100 cc. of dioxane and 16.05 The precipitated potassium carbonate is filtered off and g. (0.071 mol) of N-[ 8(1-ethy1-2-oxo-imidazolidyl)- the alcohol is distilled off on a steam bath. The residue ethyll-piperazine and 7.17 g. (0.071 mol) of triethylis treated with a 40% aqueous solution of sodium hyamine are added thereto. The mixture is heated to boildroxide and the thus separating oil is extracted several ing under reflux for 16 hours. The N-[fl-(1-ethyl-2-oxotimes with benzene. The combined benzene extracts are imidazolidyD-ethyl]-piperazine has been prepared as dedried over potassium carbonate and are evaporated on scribed in Example 1 from 1-ethyl-3-B-chloroethyl-imidaa steam bath. The resulting residue is distilled in a high zolidone-(Z) and mono-N-carbethoxy-piperazine. vacuo. 16 g. of N-[fl-(l methyl-2-oxo-imidazolidyl)- The reaction mixture is worked up as described in Exethyl]-piperazine are obtained. Yield: 71.15% of the 25 ample 2. Thus, 3-chloro-10-[1-(1"-ethyl-2"-oxo-3"- theoretical. ethyl-imidazolidyl)-4-piperazino-n-propyl] phenthiazine The homologous compounds are produced in an base is obtained. B.P. 260-265 C. Yield: 19 analogous manner. g. (53.57% of the theoretical).

The physical data of these compounds are given in the For preparing the dihydrochloride, the base is dissolved following Table 1: in anhydrous ether and ethereal hydrogen chloride is TABLE 1 N-[B-(Lmethyl-2-ox0imidazolidyl)-etl1yl]-piperazine B.p.o.ot mm-I 155-158 C no: 1.5153

HN N- (C H2) z-N O N-CH3 N-[B-(1-ethyl-2-oxoimidazolidyl)-ethyl]-piperazine B.p.o.ut rum-1 160-165" C no: 1.5111

H-N N(CH2)2N O N-CzHs N-[y-(1-methyl-2oxoimidazolidyl)-n-propyl]-pipera- B.p.u.oz tum-r 165170 C up: 1.5140

H-N N(OH2):N -o

N-CH:

N-[y-(1-ethy1-2-oxoimidazolidyl)-n-propyl]-piperazine B.p.0-01 m: 168-170 C H-N N( 0 Hz) 3-N= O N-C2H5 The yields range between and 72% of the theoretical. slowly added to this solution while cooling. The precip- Example 2.-3-chlor0-10-[1'(1"-methyl-Z"-0x0-3-ethyli gg g gigfigg gz g tg x q g? and i l x ramrx re -C0l'1S1S1I1g mu azol y p [P mazmo n p'opyl] phenth mZ me of acetone and a small amount of methanol. F.: 215- 23 g. of 3-chloro-10-( -chloropropyl)-phenth1azme are 65 216 C. dissolved in 100 cc. of dioxane and 15.36 g. of N-[B- (1-methy1-2-o-xo-imidazolidyl)-ethyl]-piperazine obtained Examplel 1- 21 (1 -n:lethyl-2. -0xo-3 -naccording to Example 1 and 7.49 g. of triethylamine are f x azol y added thereto. The mixture is heated to boiling under tuazme reflux for 12 hours. After cooling, the precipitated tri- 24.8 g. (0.08 mol) of 3-chloro-10- -chloropropyl)- ethylamine hydrochloride is filtered off and the solvent is distilled off in a vacuo. The resulting residue is mixed with ether, the ethereal layer is washed several times with water and finally dried over potassium carbonate. After having distilled Off the ether, the resulting residue is 7 ing under reflux for 12 hours.

phenthiazine are dissolved in cc. of dioxane and 18 g. (0.08 mol) of N-[v-(l-methyl 2 -oxo-imidaZolidyl)-npropyl]piperazine and 8.1 g. (0.08 mol) of triethylamine are added thereto. The mixture is heated to boil- The N-[y-(l-methyl-Z- Example 5 .3-ch l 01-0-1 [1 1 "-etlzyl-Z "-0x0-3 "-n-propyl-imidazolidyl) -4-piperazin0-n-propyl1-phenthiazine 24 g. (0.077 mol) of 3-chloro-10-( -chloropropyl)- phenthiazine are dissolved in 100 cc. of dioxane and 18.60 g. (0.077 mol) of N-['y-(1-ethyl-2-oxo-imidazolidyl)-n-propyl]-pipera2ine and 7.82 g. (0.077 mol) of triethylamine are added thereto. The mixture is heated to boiling under reflux for 12 hours. The N-[y-(l-ethyl-Z- oxo-imidazolidyl)-n-propyl]-piperazine has been prepared as described in Example 1 from 1-ethyl-3-y-chloro-n-propyl-imidazolidone-(Z) and mono-N-carbethoxy-piperazine.. The separation and purification of the 3-chloro- 10-[1'-(1"-ethyl-2"-oxo-3 n propyl imidazolidyl)-4- piperazino-n-propyl]-phenthiazine base is carried out as described in Example 2.

B.P. approx. 270 C. Yield: 22 g. (55.30% of the theoretical).

For preparing the dihydrochloride, the base is treated with ethereal hydrogen chloride as described in Example 2 and is recrystallized from a mixture of acetone and methanol. F.: 225 C.

The dimaleate is obtained as follows:

7 g. of the base are dissolved in acetone. A solution of 5 g. of maleic acid anhydride (excess) in a small amount of water is added thereto and the mixture is allowed to stand over night. The precipitated crystais may be recrystallized from ethanol. R: 166 C. Yield: 6 g. (69.95% of the theoretical).

The phenthiazine derivatives of the eneral Formula I according to the present invention are pharmacologically interesting particularly because of their strong psychosedative and antiemetic effectiveness which in comparison to known psychosedatives and antiemetics is improved to a surprisingly high extent.

The following compounds have 'been subjected to the following pharmacological tests ad:

(1) 3-chloro-l0[l'-(1"-methy1-2"-oxo-3 "-ethyl-imidazolidyl)-4-piperazino-n-propyl] phenthiazine according to Example 2;

(2) 3-chloro-10-[1'-(1"-ethy1-2"-oxo-3"-ethyl imidazolidyl)-4'-piperazino-npropyl]phenthiazine according to Example 3.

(a) The test compounds were administered subcutaneously to rats for testing their sedative eifectiveness. The test animals were regarded as sedated if they showed neither spontaneous mutility nor are caused to move by weak mechanical stimulus (by pushing) (Table 2).

TABLE 2.SEDATIVE EFFECTIVENESS ON RATS; S. C.

Test Compound N0. DE 95 (,umoL/kg.)

6 bital-Na. The reappearance of the retrogate reflex was used as the time of termination of the narcosis (Table 3).

TABLE 3.NARCOSIS PBKZIICIENGT NG EFFECTIVENESS ON Dose 1 rnoL/kg.)

Dose effecting a 100% prolongation of the duration of HZII'COSIS.

(c) In order to examine the hypothermic eifectiveness of the compounds on rats, the dose which produced an average decrease of the normal body temperature for 1.0 C. after subcutaneous application was determined (Table 4).

TABLE 4.HYPOTHERMIC EFFECTIVENESS ON RATS; S.C

Test Compound N 0. DE 1.0 C.

(#moL/k J TABLE 5.ANTIEMETIC EFFECTIVENESS ON DOGS; 8.0

Test Compound No. DE (nmoL/kg.)

The toxicity tests on rats (s.c.) showed that all of the test compounds have a rather low toxicity.

TABLE 6.TOXICITY Test Compound No. DL 50+ (,umoL/kg.)

+ Seven days test.

From these toxicity Values the therapeutic index regarding the sedative and the antiemetic effectiveness may be calculated as follows:

TAB LE 7.1HE RAPEUTIC INDEX Therapeutic Index (DL 50/DE 95) Test Compound N 0 Sedative Effectiveness Antiemetic Effectiveness on Rats, so. on Dogs, so.

What we claim is: 1. A compound selected from the group consisting of the phenthiazine derivative of the Formula I wherein R is a member selected from the group consisting of ethyl and methyl and n is a numeral selected from the group consisting of 2 and 3, and the salt thereof with a pharmacologically acceptable acid.

2. A compound selected from the group consisting of 3-chloro-10-[1-(l-methyl-2" X0 3"-ethyl-irnidazolidyl)-4-piperazino-n-propyl]-phenthiazine and the salt thereof with a pharmacologically acceptable acid.

3. A compound selected from the group consisting of 3-chloro-'l0-[1 (1"-ethyl-2" OX0 3-ethyl-imidazolidyl)-4'-piperazino-n-propyl]-phenthiazine and the salt thereof with a pharmacologically acceptable acid.

4. A compound selected from the group consisting of 3-chloro-10-[1'-|( 1"-methyl-2" oxo 3"-n-propyl-imidazolidyl)-4-piperazino n propyl]-phenthiazine and the salt thereof with a pharmacologically acceptable acid.

5. A compound selected from the group consisting of 3-ehloro-10-[1-(1"-ethy1-2" oxo 3"-n-propy1-imidazolidyl)-4-piperazino n propyl]-phenthiazine and the salt thereof with a pharmacologically acceptable acid.

6. 3 chloro -1O [1' (1" methyl 2" oxo 3"- ethyl imidazolidyl) 4' piperazino n propyl] phenthiazine.

7. 3 chloro [1-(1-ethyl 2" oxo 3 ethylimidazolidyl)-4'-piperazino-n-propyl]-phenthiazine.

8. 3 chloro 10 [1 (1" methyl 2" 0X0 3"- n propyl imidazolidyl) 4' piperazino n propyl]- phenthiazine.

9. 3 chloro -1O [1' (1" ethyl 2 OX0 3" npropyl imidazolidyl) 4 piperazino n propyl] -phenthiazine.

10. 3 chloro 1O [1 (1" methyl 2" 0x0 3"- ethyl imidazolidyl) 4' piperazino n propyl] -phenthiazine dihydrochloride.

11. 3 chloro 10 [1' (l"- ethyl 2" oxo 3"- ethyl imidazolidyl) 4' piperazino n propyl] phenthiazine dihydrochloride.

12. 3 chloro l0 [1 (1" methyl 2" oxo-3"- n propyl imidazolidyl) 4 piperazino n propyl]- phenthiazine dihydrochloride.

13. 3 chloro 10 [1 (1" ethyl 2" oxo 3"- n propyl imidazolidyl) 4 piperazino n propyl]- phenthiazine dihydrochloride.

No references cited.

WALTER A. MODANCE, Primary Examiner.

HARRY I. M-OATZ, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE PHENTHIAZINE DERIVATIVE OF THE FORMULA I 